Diagnosis and management of asthma]

Asthma is a chronic inflammatory disorder of the airways with many inflammatory cells such as eosinophils, mast cells, T lymphocytes and basophils. This inflammation causes airflow limitation, airway hyperresponsiveness, respiratory symptoms and disease chronicity. Long-term-control medication are needed to prevent and control asthma symptoms.     

Therapeutic modulation of allergic airways disease with leukotriene receptor antagonists

Although asthma is one of the most common chronic respiratory conditions, it often remains unrecognized and undertreated, while patients are often reluctant to comply with regular inhaled anti-inflammatory and bronchodilator therapy. Allergic rhinitis co-exists with asthma in as many as 40% of patients, and can be regarded as a continuum of the same inflammatory disease process. Corticosteroids are the 'gold standard' first-line treatment for both conditions, and have a significant impact upon underlying inflammation, symptoms and long-term outcome. Cysteinyl leukotrienes are potent airway inflammatory mediators, suggesting that treatment antagonizing their effects could play a role in disease management. In recent years, leukotriene receptor antagonists have provided a further therapeutic option in the management of allergic airways disease. These drugs are orally active, can be administered once daily, and provide a systemic approach to the management of patients with asthma and allergic rhinitis. We review the pharmacology of leukotriene receptor antagonists, their potential role in clinical practice in patients with allergic airways disease, and likely areas for further research.     

Evidence-based hypnotherapy for asthma: a critical review

Asthma is a chronic disease with intermittent acute exacerbations, characterized by obstructed airways, hyper-responsiveness, and sometimes by chronic airway inflammation. Critically reviewing evidence primarily from controlled outcome studies on hypnosis for asthma shows that hypnosis is possibly efficacious for treatment of symptom severity and illness-related behaviors and is efficacious for managing emotional states that exacerbate airway obstruction. Hypnosis is also possibly efficacious for decreasing airway obstruction and stabilizing airway hyper-responsiveness in some individuals, but there is insufficient evidence that hypnosis affects asthma's inflammatory process. Promising research needs to be replicated with larger samples and better designs with careful attention paid to the types of hypnotic suggestions given. The critical issue is not so much whether it is used but how it is used. Future outcome research must address the relative contribution of expectancies, hypnotizability, hypnotic induction, and specific suggestions.     

Evaluation of functional,autonomic and inflammatory outcomes in children with asthma

Asthma is common in childhood. This respiratory disease is characterized by persistent inflammation of the airways even when the child is not in thethroes of an attack. Chronic inflammation is caused by an imbalance between pro-inflammatory and antiinflammatory mechanisms as well as autonomic dysfunction, which plays an important role in the pathogenesis and control of this condition. The impact of these physiopathological aspects leads to inactivity and a sedentary lifestyle, which exerts an influence on functional capacity and control of the disease. The main objective of non-pharmacological therapy is the clinical control of asthma and the minimization of airway obstruction and hyperinflation during an attack. These factors can be controlled with noninvasive ventilation. The aim or the present review was to describe important neural, inflammatory and functional mechanisms that affect children with asthma.     

An overview of drug therapy for chronic adult asthma.

Asthma involves bronchoconstrictor mechanisms, possible abnormalities of airway smooth muscles and an inflammatory response. Past emphasis on bronchodilator therapy ignored the underlying inflammatory response. Since chronic asthma can eventually lead to irreversible airflow obstruction from uncontrolled inflammation, current drug therapy stresses both inflammation reduction and bronchodilatation. This article discusses the rationale of current pharmacologic management for the adult client with chronic asthma and presents a step-care approach for management of the disease. Inhaled beta-agonists--effective bronchodilators--are the primary drug of choice. Steroids administered via inhalation are the most effective anti-inflammatory agents available. Cromolyn sodium is useful for prophylactic management of asthma. Theophylline, previously the cornerstone of asthma treatment, is now introduced later in the therapeutic plan as an additional bronchodilator. Inhaled anticholinergics may be tried as adjunctive asthma treatment. With careful assessment, intervention and management, health care providers can successfully care for most adult clients with chronic asthma.     

Inflammatory mechanisms and treatment of obstructive airway diseases with neutrophilic bronchitis

Obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major global health issues. Although considered as distinct diseases, airway inflammation is a key underlying pathophysiological process in asthma, COPD and bronchiectasis. Persistent neutrophilic airway inflammation (neutrophilic bronchitis) occurs with innate immune activation and is a feature of each of these airway diseases. Little is known about the mechanisms leading to neutrophilic bronchitis and few treatments are effective in reducing neutrophil accumulation in the airways.There is a similar pattern of inflammatory mediator release and toll like receptor 2 expression in asthma, COPD and bronchiectasis. We propose the existence of an active amplification mechanism, an effector arm of the innate immune system, involving toll like receptor 2, operating in persistent neutrophilic bronchitis.Neutrophil persistence in the airways can occur through a number of mechanisms such as impaired apoptosis, efferocytosis and mucus hypersecretion, all of which are impaired in airways disease. Impairment of neutrophil clearance results in a reduced ability to respond to bacterial infection. Persistent activation of airway neutrophils may result in the persistent activation of the innate immune system resulting in further airway insult.Current therapies are limited for the treatment of neutrophilic bronchitis; possible treatments being investigated include theophylline, statins, antagonists of pro-inflammatory cytokines and macrolide antibiotics. Macrolides have shown great promise in their ability to reduce airway inflammation, and can reduce airway neutrophils, levels of CXCL8 and neutrophil proteases in the airways. Studies also show improvements in quality of life and exacerbation rates in airways diseases.     

The cytokine network in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.     

TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis

TNF-alpha (tumour necrosis factor-alpha) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-alpha is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-alpha are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-alpha in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-alpha in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-alpha have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-alpha are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-alpha in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-alpha may also be useful in the management of chronic severe asthma.     

Role of protease-activated receptors in airway function: a target for therapeutic intervention?

Protease-activated receptors (PARs) are G-protein-coupled, seven transmembrane domain receptors that act as cellular enzyme sensors. These receptors are activated by the proteolytic cleavage at the amino terminus, enabling interaction between the newly formed "tethered ligand" and the second extracellular loop of the receptor to confer cellular signalling. PARs can also be activated by small peptides that mimic the tethered ligand. In the respiratory tract, PARs may be regulated by endogenous proteases, such as airway trypsin and mast cell tryptase, as well as exogenous proteases, including inhaled aeroallergens such as those from house dust mite faecal pellets. Immunoreactive PARs have been identified in multiple cell types of the respiratory tract, and PAR activation has been reported to stimulate cellular mitogenesis and to promote tissue inflammation. Activation of PARs concurrently stimulates the release of bronchorelaxant and anti-inflammatory mediators, which may serve to induce cytoprotection and to minimise tissue trauma associated with severe chronic airways inflammation. Furthermore, airway inflammatory responses are associated with increased epithelial PAR expression and elevated concentrations of PAR-activating, and PAR-inactivating, proteases in the extracellular space. On this basis, PARs are likely to play a regulatory role in airway homeostasis, and may participate in respiratory inflammatory disorders, such as asthma and chronic obstructive pulmonary disease. Further studies focussing on the effects of newly developed PAR agonists and antagonists in appropriate models of airway inflammation will permit better insight into the role of PARs in respiratory pathophysiology and their potential as therapeutic targets.     

Biological markers in diagnosing, monitoring, and treating asthma: a focus on noninvasive measurements

Asthma is a major concern for society, healthcare professionals, and individuals and families directly affected by asthma due to rising morbidity rates and costs associated with the disease. The pathological hallmark of asthma is airway inflammation that is considered to be a major cause of exacerbations and persistent structural alterations of the airways. Assessing airway inflammation is important for investigating the underlying mechanisms of the disease and possibly for following the progression and resolution of the disease. The presence and type of airway inflammation can be difficult to detect clinically, and may result in delays in initiating appropriate therapy. The purpose of this article is to review noninvasive methods for assessing biological markers of airway inflammation and their potential role in the future for diagnosing, monitoring, and treating asthma. The article reviews the noninvasive measurements of induced sputum and exhaled nitric oxide as indicators of airway inflammation.     

What is the best pulmonary diagnostic approach for wheezing patients with normal spirometry?

Asthma is characterized by airway inflammation, airway hyper-responsiveness (AHR) and variable air flow obstruction. The diagnosis of asthma, however, is often based upon nonspecific clinical symptoms of cough, wheeze, and shortness of breath. Furthermore, the physical examination and measurements of pulmonary function are often unremarkable in patients with asthma, thereby complicating the diagnosis of the disease. The following discussion will review approaches to the diagnosis of asthma when lung functions are normal, and will largely focus on the use of bronchial provocation tests to detect underlying AHR.     

Bronchial hyperresponsiveness and bacterial respiratory infections.

Some studies suggest a potential role for bacterial respiratory tract infections in the development of bronchospasm and the progression of chronic obstructive pulmonary disease (COPD). Patients with bronchiectasis or cystic fibrosis have exaggerated airway reactivity; croup in children can also cause exaggerated upper and lower airway responsiveness. Bronchial obstruction after inhalation of Haemophilus influenzae and other bacteria has been reported. Between January 1989 and June 1990 we and two other centers studied 193 patients suffering from acute exacerbation of asthma. Fifty-two (27%) of these patients had bacteria in their sputum. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis, and H influenzae were the most commonly isolated bacterial species. Antibiotics may be of value in the treatment of infective lung disease, not only by killing bacteria but also by preventing increases in bacterial histamine levels within the lung airways. Moreover, an antibiotic of proven efficacy can reduce airway reactivity in patients with bacterial exacerbations of COPD or bronchial asthma. In 12 patients with acute bacterial exacerbation of asthma and high airway reactivity to methacholine, a ten-day course of treatment with cefaclor and existing bronchodilators induced microbiologic cure and a slight but nonsignificant change in airway reactivity in nine patients. Antibiotic therapy has a minor but clear role in the control of acquired bronchial hyperreactivity during bacterial respiratory infections in asthmatic patients; however, because of airway inflammation, an antibiotic's efficacy is evident only when the inflammatory process subsides. Approaches designed to minimize airway reactivity may contribute to the prevention or reversal of respiratory failure during exacerbation of COPD and bronchial asthma.     

Type 4 phosphodiesterase inhibitors attenuate respiratory syncytial virus-induced airway hyper-responsiveness and lung eosinophilia

Viral respiratory infections are considered one of the triggers of exacerbations of asthma. In a model of virus-induced airway hyper-responsiveness (AHR), mice infected with human respiratory syncytial virus (RSV) were shown to develop AHR accompanied by lung eosinophilia. Inhibitors of cyclic nucleotide phosphodiesterase (PDE) have been shown to affect airway responsiveness and pulmonary allergic inflammation. In this study, we assessed the effects of type 4 PDE (PDE4) inhibitors on AHR following RSV infection and compared them with a PDE3 inhibitor. In mice infected by intranasal inoculation of RSV, treatment with the PDE4 inhibitor rolipram or Ro-20-1724 reduced both AHR and the eosinophil infiltration of the airways. In contrast, the PDE3 inhibitor, milrinone, did not influence airway responsiveness or eosinophilic inflammation. These results demonstrate that PDE4 inhibitors can modulate RSV-induced AHR and lung eosinophilia and indicate that they have a potential role in treating exacerbations of asthma triggered by viral infection.     

New insights into the relationship between airway inflammation and asthma

Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.     

Pathogenesis of asthma

The conception of the pathogenesis of a disease is probably as important in determining the selection of therapies as is the evidence provided by outcome studies of their efficacy. The recent evolution in our understanding of the pathogenesis of asthma has nicely paralleled advances in clinical research on new forms of treatment. This evolution has occurred so smoothly that we may not be fully aware how far it has taken us. Airflow obstruction is still regarded as the fundamental cause of the characteristic asthmatic symptoms of shortness of breath, chest tightness, and wheezing, while the factors leading to airflow obstruction are still assumed to include spasm of airway smooth muscle, thickening of the airway wall, and inspissation of viscid plugs of mucus in the airway lumen. What is new is the recognition of asthma as a chronic disease of the lower airways associated with characteristic inflammatory changes (involving lymphocytes, mast cells, and eosinophils), and possibly irreversible "remodeling" of the airways (by deposition of collagen and proteoglycans, proliferation and transformation of resident cells, and infiltration with inflammatory cells). This modern conception of asthma differs dramatically from the former perception of the disease as an episodic illness characterized by disturbance of the contractile function of airway smooth muscle. The new interpretation has important implications not just for the development of future therapies based on the inflammatory mechanisms involved in the pathogenesis of asthma, but also for the ways in which current therapies should be used.     

Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial–mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments.     

Biologic markers of airway inflammation in asthma

Asthma is a serious chronic disease of the airways that affects approximately 14% of the population in the United States. The fundamental pathophysiologic component of asthma is airway narrowing, which causes airflow obstruction. Both inflammation and bronchoconstriction contribute to airway narrowing. The pathogenesis of airway inflammation in asthma and the natural history of the disease are the subject of intense research and study in many countries of the world. The mechanisms of airway inflammation are only partially understood but are the basis for the devastating symptoms that affect the quality of life of millions of people. Treatment of asthma is directed at decreasing airway inflammation to gain long-term control of the disease.     

Budesonide/formoterol decreases expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 within airway remodelling in asthma

INTRODUCTION: Angiogenesis and microvascular remodelling may play a vital role in the chronic inflammatory process within asthma. One of the most important factors involved in angiogenesis is vascular endothelial growth factor (VEGF). In this study we hypothesised that an increased expression of VEGF may be involved in airway remodelling in asthma patients. To this end, we compared the histology and expression levels of VEGF and one of its receptors (VEGFR1) in bronchial tissues of patients with asthma compared with control patients. We also investigated the effect of treatment with budesonide/formoterol (Symbicort(R); AstraZeneca, Lund, Sweden) in the relationship between VEGF and airway remodelling. METHODS: Bronchial tissues were obtained from patients attending the West China Hospital from April to November 2006. Thirteen patients were diagnosed with moderate asthma and 10 others were treated as control. Histological and immunohistochemical comparisons between asthmatic and control patients were made at baseline, and (for asthmatic subjects) following 6 months of treatment with budesonide/formoterol. RESULTS: Compared with control patients, asthmatic patients had significantly decreased respiratory parameters, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) (% predictive). Furthermore, patients with asthma had submucosal gland hyperplasia, increased smooth muscle mass, increased subepithelial fibrosis and neovascularisation. Asthmatic patients also exhibited increased expression of VEGF and VEGFR1 within epithelial cells. The increased expression of VEGF and its receptor correlated well with airway remodelling, airflow obstruction and airway hyper-responsiveness. After treatment with budesonide/formoterol for 6 months, the expression of VEGF and VEGFR1 was decreased, with correlatory decreased airway remodelling in patients with asthma. CONCLUSION: The increased expression of VEGF and VEGFR(1) in asthmatic patients is accompanied by an increased number and size of blood vessels in asthmatic airways, as well as airway remodelling. Budesonide/formoterol therapy for 6 months can decrease the expression of VEGF and VEGFR(1) alongside airway remodelling in asthma. The inhibition of VEGF and its receptor may be a good therapeutic strategy for asthma.     

Microbiota abnormalities in inflammatory airway diseases — Potential for therapy

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of ‘health-promoting’ bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.     

The role of the NLRP3 inflammasome in the pathogenesis of airway disease

The incidences of respiratory diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD) are increasing dramatically. Significantly, there are currently no treatments that can slow or prevent the relentless progression of COPD; and a sub-population of asthmatics are resistant to available therapies. What is more, currently prescribed medication has only minimal effect on the symptoms suffered in these patient groups. There is therefore an urgent need to develop effective drugs to treat these diseases. Whilst asthma and COPD are thought to be distinct diseases, it is currently believed that the pathogenesis of both is driven by the chronic inflammation present in the airways of these patients. It is thus hypothesised that if the inflammation could be attenuated, disease development would be slowed and symptoms reduced. It is therefore paramount to determine the pathways driving/propagating the inflammation. Recently there has been a growing body of evidence to suggest that the multimeric protein complex known as the Inflammasome may play key roles in the inflammation observed in respiratory diseases. The aim of this review is to discuss the role of the NLRP3 Inflammasome, and its associated inflammatory mediators (IL-1β and IL-18), in the pathogenesis of asthma and COPD.